A Breakthrough in a Disease That No One Likes To Talk About

Over the years, Linda Griffith, a biological engineer at the Massachusetts Institute of Technology, has undergone nine surgeries for endometriosis. In women with the disease, tissue that normally lines the uterus grows elsewhere in the body—for instance, on the ovaries, bladder, or bowel—often causing pain, infertility, or both. In early-stage cases, patients have small lesions, usually accompanied by inflammation; if the disease progresses, scar tissue may cause one organ to stick to another. The bladder might attach to the uterus, or the ovary might attach to the bowel. It’s “like someone poured superglue into the pelvis, and organs that normally are free to move around are, all of a sudden, just stuck,” Keith Isaacson, a gynecologist and surgeon at Newton-Wellesley Hospital, in Massachusetts, said. He operated several times on Griffith, a MacArthur fellowship recipient, and is now her scientific collaborator.

In 2006, he started “nagging me to work on endometriosis,” Griffith, who had previously focussed on liver-tissue engineering and bone regeneration, said. (She also once helped to make an ear that was grown on the back of a mouse.) In 2009, she and Isaacson became the co-directors of a new center at M.I.T. that is devoted to studying gynecological diseases. In early February, they published a major paper, taking “an engineering approach to endometriosis,” as Griffith put it. Specifically, they analyzed how a whole network of cells and molecules interacts in some patients to cause inflammation, which triggers pain and may also spur the disease’s progression. They also identified ways in which new drugs might someday help to quiet that signalling.

“It’s a much more comprehensive approach to understanding endometriosis than anyone’s done in the past,” Hugh Taylor, the chair of the department of obstetrics, gynecology, and reproductive sciences at the Yale School of Medicine, said.

Researchers don’t know with certainty what causes the disease. One theory blames menstrual blood that flows in the wrong direction, through the fallopian tubes and into the abdominal cavity. In some women, cells from this flow that are not cleared by the immune system can start to grow on the body’s internal walls, or on organs such as the ovary and bowel. Another theory suggests that cells already in the abdominal cavity become more like uterine cells, for reasons that are not clear, and proliferate. In either case, these cells trigger inflammation which contributes to discomfort and possibly the worsening of the disease, Isaacson said. As lesions grow, they can spur the development of new nerves or burrow against existing ones, causing further misery.

Inflammation, of course, is a “big, messy problem,” involving a host of molecules and cells, Griffith said. Rather than look at proteins or markers one at a time, “our approach was to try to organize the landscape.” She and her team studied pelvic fluid taken from women who were undergoing surgery for endometriosis. They probed the fluid for fifty immune proteins and found a group of thirteen that seemed to increase together, suggesting that they were acting in concert. The researchers then looked at clinical data for women whose pelvic fluid contained elevated levels of these proteins. They found that women with this pattern were more likely to report higher levels of pain and fewer successful pregnancies than women without it. In other words, they’d found proteins that were acting together, and they’d shown that people with more of these proteins were suffering greatly. The findings represent a “very thorough, unbiased way to look at the disease,” Kevin Osteen, a professor of obstetrics and gynecology at Vanderbilt University’s medical school, said.

The work also hints at potential new treatments. No new drugs for endometriosis have been approved in decades, and most of the current ones target hormones that can fuel the growth of uterine tissue. “The first line is always a birth-control pill,” said Taylor. This approach seems to work for some women, reducing pain and perhaps stopping the growth of lesions, but not for everyone, and sometimes its effectiveness wanes. Patients also commonly use drugs like ibuprofen, which target inflammation but are not specifically designed to treat endometriosis. The M.I.T. group’s work suggests that it might be possible to reduce inflammation in a more targeted way in some patients with the disease.

The results must be replicated, of course, and it remains to be seen whether they will hold up in larger groups of women at different ages or with different symptoms, Osteen said. As usual, it’s hard to predict whether basic science will someday translate into successful new drugs.

But the study is important because it shows the power of a new method now being used to probe a complex disease. The type of modelling championed by the M.I.T. group represents a move away from reductionism and toward an effort to “embrace the complexity of biological systems,” Kevin Haigis, an expert in systems biology at Harvard Medical School, said. The researchers worked with tissues that came from patients, rather than cells cultured in a petri dish, meaning that they were able to probe how cells behaved in their native environment. They then used multivariate mathematical modelling to identify the group of signals correlated with the disorder. That analysis is what gives the work an engineering flavor, Haigis said. This method is especially well-suited to vexing problems like inflammation, which is a hallmark of many diseases. One of the best examples is endometriosis.

This is a remarkable development for a disorder that has existed largely in the shadows. It has never been an easy one to discuss, after all. It often emerges in the form of painful periods or pain during sex. It can also trigger gastrointestinal problems, such as diarrhea and constipation, when uterine tissue grows on the bowel. To diagnose it definitively, women must undergo surgery and have the excised tissue analyzed. A few years ago, Griffith said her niece exhibited classic symptoms that her female gynecologist “completely dismissed. … My sister was told she was making up symptoms to get out of school. But my niece loved school.” Even in scientific circles, it can be hard to talk seriously about the disease and its debilitating effects. Scientists will “talk about breast cancer without batting an eye. But you cannot talk about menstrual problems,” Griffith said. “It’s the third rail, and that needs to change.”